It is estimated that 75% of prostatic cancers are sensitive to levels of androgens, more specifically testosterone. (Van Wauwe, J. P. and Janssen, P. A. J., J. Med. Chem., (1989), 32, 2233). It is well established that reduction of serum testosterone levels is useful in the treatment of such prostatic cancers. In clinical practice, this has been accomplished for example by orchiectomy or by diethylstilbestrol treatment. However, the first approach is often psychologically unacceptable while a number of side effects are associated with the second approach.
The cytochrome P-450.sub.17.alpha. monooxygenase enzyme system catalyzes the 17.alpha.-hydroxylation of C.sub.21 steroids and also catalyzes the oxidative cleavage of the C.sub.17-20 bond. (Blohm, T. R. et al., Biochem. Biophys. Res. Commun., (1989), 162, 1571). More specifically the steroid C.sub.17-20 lyase activity of cytochrome P-450.sub.17.alpha. catalyzes the conversion of the C.sub.21 steroids pregnenolone and progesterone to the C.sub.19 steroids dehydroepiandrosterone and androstenedione, which are the precursors of the androgens, 5.alpha.-dihydrotestosterone and testosterone. Androstenedione and testosterone, in turn, are the precursors of the estrogens, estrone and estradiol. Thus, inhibition of the steroid C.sub.17-20 lyase can reduce formation of the androgens as well as the estrogens. As a result of this effect, the search for effective and selective inhibitors of the steroid C.sub.17-20 lyase enzyme is expanding. (Laughton, C. A. and Neidle, S., Biochem. Biophys. Res. Commun., (1990), 171, 1160). C.sub.17-20 lyase inhibitors would be useful for treating various androgen-dependent disorders. More particularly, such compounds would be useful in the treatment of prostatic carcinoma, benign prostatic hyperplasia, male-pattern baldness and virilism and hirsutism (in women). In addition, C.sub.17-20 lyase inhibitors would also be useful in the treatment of estrogen-dependent disorders, such as estrogen dependent breast cancer.
Thus, in light of the drawbacks associated with diethylstilbestrol treatment or orchiectomy, there has been an ongoing search for effective inhibitors of steroid C.sub.17-20 lyase. The present invention relates to C.sub.17 heterocyclic steroids and also to a method for using such compounds as effective steroid C.sub.17-20 lyase inhibitors. More particularly, the present invention relates to the treatment of androgen dependent disorders.